The association between neutrophil-to-albumin ratio and mortality in patients with cardiogenic shock: a cohort study

Background Cardiogenic shock (CS) is a lethal complication. Given the poor outcome of CS, we performed a retrospective cohort study to identify whether the neutrophil-to-albumin ratio (NAR) was significantly associated with mortality from CS. Methods All patient data were extracted from the MIMIC III version 1.3. Comparisons between groups was made using the chi-square or Fisher’s exact tests for categorical variables and the variance analysis or the Kruskal-Wallis test was used for continuous variables. The primary outcome was 30-day mortality and the secondary ones were 90-day and 365-day mortality. We used Cox proportional hazards models to evaluate the association between the various categories of NAR and survival. To further identify the association, subgroup analyses were performed. Results A total of 475 patients with CS were enrolled. A significant positive correlation between NAR levels and 30-day, 90-day or 365-day mortality was observed. For the primary outcome of 30-day mortality, the HR (95% CI) values given NAR levels 23.54–27.86 and > 27.86 were 1.72 (1.17, 2.53) and 1.96 (1.34, 2.87) compared with the reference (NAR < 23.47) in tertile analysis. In multivariate analyses, the HR (95% CI) values were still of statistical significance1.98 (1.25, 3.15) and 2.03 (1.26, 3.26). When quintiles were applied to grouping patients according to NAR level, similar associations were also observed. For the secondary outcomes, the upward trend remained statistically significant. Conclusions NAR level was associated with survival from CS. NAR appeared to be an independent and readily-available prognostic biomarker of mortality in patients with CS.


Abstract
Background Cardiogenic shock (CS) is a lethal complication. Given the poor outcome of CS, we performed a retrospective cohort study to identify whether the neutrophil-toalbumin ratio (NAR) was significantly associated with mortality from CS. Methods All patient data were extracted from the MIMIC III version 1.3. Comparisons between groups was made using the chi-square or Fisher's exact tests for categorical variables and the variance analysis or the Kruskal-Wallis test was used for continuous variables. The primary outcome was 30-day mortality and the secondary ones were 90-day and 365-day mortality. We used Cox proportional hazards models to evaluate the association between the various categories of NAR and survival. To further identify the association, subgroup analyses were performed. Results A total of 475 patients with CS were enrolled. A significant positive correlation between NAR levels and 30-day, 90-day or 365-day mortality was observed. For the primary outcome of 30-day mortality, the HR (95% CI) values given NAR levels 23 (1.26, 3.26). When quintiles were applied to grouping patients according to NAR level, similar associations were also observed. For the secondary outcomes, the upward trend remained statistically significant. Conclusions NAR level was associated with survival from CS. NAR appeared to be an independent and readily-available prognostic biomarker of mortality in patients with CS.

Background
Cardiogenic shock (CS), a lethal complication of cardiac emergencies, is traditionally thought to begin with depression of myocardial contractility, followed by intractable hypotension, coronary insufficiency and further loss of cardiac output, causing multiple organ failure and eventually death 1,2 . For decades, the prevalence of CS has risen from 4.1% to 7.7% of all admissions to the intensive care unit (ICU) 3 , of which approximately 6.4% to 40% were reported to have died despite intensive care 4,5 . Although less frequent than other fatal diseases, CS has had even higher mortality rates and poorer short-term survival, remaining a clinical challenge for medical personnel throughout the world [6][7][8] .
Previous studies have shown that a systemic inflammatory response, release of cytokines, activation of complement, expression of inducible nitric oxide synthase and improper vasodilatation might exert an influence both on the occurrence and the outcome of shock 9 . Further evidence suggested that inflammation played an important role in the pathogenesis and outcome of CS, a devastating complication of cardiovascular diseases 10 . Among the inflammatory mediators, the neutrophil is well-known as a marker of inflammation 11 . Several studies indicated that low serum albumin levels were associated with high mortality because of all-cause or cardiovascular mortality 12,13 .
Based on these studies, we put forward a hypothesis that neutrophil-to-albumin ratio (NAR) would be associated with mortality from CS. To our knowledge, to date, no study has explored the prognostic significance of NAR in patients with CS. Therefore, we performed a retrospective cohort study to identify the associations between NAR and mortality in patients with CS so as to assess prognosis.

Data source
All data in our study were extracted from the Medical Information Mart for Intensive Care  14 . The setting and use of this database were approved by the institutional review boards of the Massachusetts Institute of Technology (Boston, MA) and Beth Israel Deaconess Medical Center (Cambridge, MA). All personal information included in the database have been de-identified to safeguard privacy.

Population selection criteria
More than 50,000 ICU admissions to the MIMIC-III database were recorded, and only patients diagnosed with CS were extracted. Among these patients, we selected those who attained more than 16 years of age at first admission while remaining in the hospital for more than 48 hours. Exclusion criteria were as follows: (1) patients who were diagnosed with hematologic neoplasms, including leukemia, multiple myeloma, and others; (2) more than 10% individual data were missing; (3) individual data values exceeded the mean ± 3 times the standard deviation (SD).

CS was determined on the grounds of International Classification of Diseases, Ninth
Revision (ICD-9), the definitions in the clinical practice guidelines including the ESC Guidelines 15 as well as clinical trials, including SHOCK 16 and IABP-SHOCK II 17 .

Date extraction
Data were extracted through Structured Query Language (SQL) 18 with MySQL tools (version 5.6.24) from MIMIC-III. The extracted data contain demographic parameters, basic vital signs, laboratory indicators and scoring systems.
Demographic parameters included age, gender and ethnicity, while basic vital signs included heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), respiratory rate (RR), temperature and percutaneous oxygen saturation (SPO 2 ). The following laboratory indicators were extracted: neutrophils, albumin, platelets, partial thromboplastin time (PTT), prothrombin time (PT), international normalized ratio (INR), serum bicarbonate, serum sodium levels, serum potassium levels and serum glucose levels. We defined the NAR as the ratio of the neutrophil percentage to the serum albumin level. We additionally extracted relevant comorbidities, for example, coronary heart disease (CAD), congestive heart failure (CHF), atrial fibrillation (AF), stroke, chronic obstructive pulmonary disease (COPD), pneumonia, acute respiratory distress syndrome (ARDS) and other diseases listed in Table 1. Severity-of-illness scores, including the Sequential Organ Failure Assessment (SOFA) 19 score and the Simplified Acute Physiology Score II (SAPS II) 20 were also calculated for every individual. The SOFA score, designed to describe a sequence of complications in the critically ill, is the sum of points obtained from evaluation of respiration, coagulation, liver, cardiovascular system, central nervous system and kidney. The SAPS II, a scoring system developed to estimate the risk of death, included 12 physiology variables (HR, SBP, body temperature, partial pressure of arterial oxygen or fraction of inspired oxygen ratio, urinary output, serum urea or serum urea nitrogen level, WBC count, serum potassium level, serum sodium level, serum bicarbonate level, bilirubin level and Glasgow Coma Score 21 ), age, type of admission (scheduled surgical, unscheduled surgical or medical) and three underlying disease variables (acquired immunodeficiency syndrome, metastatic cancer and hematologic malignancy). All scores were assessed and calculated on the basis of published recommendations and accepted formulas.
The initiation of our study was the time when the patient admitted to ICU. The outcomes were 30-day, 90-day and 365-day mortality, in which 30-day mortality was the primary outcome. Baseline characteristics were all recorded within 24 hours after admission to the ICU.

Statistical analysis and modeling strategy
Baseline characteristics delaminated by NAR were presented in Table 1. Categorical data were shown as frequency (percent), while continuous ones as mean (SD) or median(IQR).
We did comparisons between groups by the chi-square test 22 or Fisher's exact test 23 for categorical variables and the variance analysis or the Kruskal-Wallis test 24 for continuous ones.
To examine the associations between NAR and outcomes (30-day, 90-day and 365-day mortality), we used Cox proportional hazards models 25 . The outcomes were respectively analysed according to the tertiles or the quintiles of the NAR level. The first tertile or quartile group was regarded as the reference group. The results were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). To further identify the association between NAR and mortality, multivariate analyses were performed using two adjusted models. The confounders selected in our models were based on their associations with mortality or a mutation exceeding 10% 26 . In model I, we adjusted covariates for age, gender and ethnicity. In model II, covariates were adjusted further for length of stay in ICU, HR, SBP, DBP, RR, SPO 2 , anion gap, serum bicarbonate, serum potassium, SCr, BUN, hematocrit, platelet count, WBC count, PTT, PT, INR, stroke, pneumonia, COPD, chronic liver disease, chronic renal disease, RRT, malignancy, vasoactive agent, SOFA score and SAPSII score. Building further on this foundation, we performed stratified analysis to confirm whether the effect of NAR differed across each of the subgroups that were classified by stay in ICU, vital signs (HR, SBP, DBP, RR, temperature, SPO 2 ), laboratory parameters (anion gap, serum bicarbonate, serum sodium, serum potassium, serum chloride, serum bilirubin, serum glucose, SCr, BUN, hematocrit, hemoglobin, platelet count, WBC count, PTT, PT, INR), comorbidities (CAD, CHF, stroke, pneumonia, COPD, respiratory failure, chronic liver disease, chronic renal disease, RRT, malignancy), vasoactive drug use and scoring systems (SOFA and SAPSII scores).
A two-tailed P value < 0.05 was deemed statistically significant. EmpowerStats version 2.17.8 (http://www.empowerstats.com/cn/) and R software version 3.42 were used for all statistical analysis.

Subject characteristics
Patient records from more than 50,000 subjects treated in the ICU at Beth Israel Deaconess Medical Center were originally extracted from the MIMIC-III database. After subjects who did not meet the inclusion criteria were excluded, a total of 475 patients with CS remained. As shown in Table 1, among the patients included, 272 (57.3%) were men and 328 (69.1%) were white.
All patients included in the study were equally divided into three groups according to NAR: Participants with higher NAR also had a higher SOFA and SAPSII scores than did those with lower NAR (< 23.47). These patients, however, had no apparent differences in age, gender, vital signs, vasoactive drug use or comorbidities listed in the Table 1.

NAR levels and mortality
A total of 180, 218 and 264 deaths were recorded in the 30-day, 90-day and 365-day follow-up periods, respectively. As shown in Table 2, we observed a positive relationship between NAR and mortality from CS.
For the primary outcome of 30-day mortality, we observed that higher NAR was associated with increased risk of mortality in tertile analysis and the HR values of the three models were all significant compared to the reference group (NAR < 23.47 The results are presented in Table 2 and Figures 1 and 2.

Subgroup analyses
Subgroup analyses were conducted to determine the consistency of association between NAR and 90-day mortality in patients with CS (Table 3).
Most subgroup factors showed weak significance with 90-day mortality, except for the length of stay in ICU (p = 0.0465), the serum sodium (p = 0.0270), the serum bilirubin (p =0.0343), respiratory failure (p = 0.0102) and RRT (p = 0.0044 in ICU, the serum sodium and the serum bilirubin, however, the interactions were of relatively weak significance. All of the subgroup analyses were demonstrated in Table 3.

Discussion
In our study, we observed a significant positive correlation between NAR levels and 30day, 90-day or 365-day mortality in patients with CS. In particular a high level of NAR was associated with growing risk of mortality. After adjusting for potential confounders, the differences in each outcome retained statistical significance.
CS is a lethal complication of cardiovascular diseases with an extremely high mortality.
Inflammation has been shown to play a vital role in the pathogenesis and outcome of CS.
Studies in recent decades have suggested the prognostic value of inflammatory mediators in CS, including blood cells 27 , cytokines 28,29 , complement 30 and enzymes 31, 32 .
Furthermore, the use of albumin, the main serum protein, to predict the mortality of cardiovascular disease as well as all-cause mortality has already been described 12,33,34 .  38 . However, whether the increase of inflammatory mediators in CS results from the heart itself, from intestinal bacterial translocation, or from ischemiareperfusion injury remains unknown 10 . On the other hand, serum albumin, synthesized in the liver, is the major plasma protein in human blood. Albumin has already been used to predict mortality especially in critically ill patients in ICUs 39,40 , and even has been a part of major risk scores, for example, the Acute Physiology and Chronic Health Evaluation (APACHE) III Prognostic system and the Framingham risk score for cardiovascular risk. Low albumin levels were demonstrated to be related to some inflammatory mediators 41, 42 ; therefore, the association between serum albumin and mortality may result from subclinical inflammation, as Mutsert et al. 43 found in their study. However, whether the prognostic value of albumin only reflects inflammation or whether there is an independent role of albumin itself remains to be turned determined. As albumin plays an important role in maintaining the plasma colloid osmotic pressure, low albumin levels may disorganize the fluid distribution in the internal environment so as to destroy the balance of the hemodynamics, resulting in poor outcomes 44 . Another interpretation may involve the state of nutrition because lower albumin is possibly related to malnutrition, emaciation or cachexia 45 . Furthermore, as the most abundant carrier protein in plasma, albumin can change the existing form of some toxins by binding to them, leading to changes in their biological effects. The recent study of Watanabe et al. 46  Our study was the first study to explore the prognostic effect of NAR in patients with CS.
The period of follow-up in our study was quite long. To further confirm the significant association between NAR and outcomes, we applied quintiles to grouping patients and performed subgroup analyses. The limitations of this study, however, cannot be ignored.
First and foremost, it was a retrospective observational study in a single center. The biases inherent in this type of study and selection bias in this design should be highlighted. Therefore, we should further perform studies based on multiple centers.
Second, owing to the relatively low incidence of CS, the sample size of patients selected in our study was small, suggesting that larger prospective studies are needed. Third, the NAR was measured only when patients first admitted to the ICU, possibly causing errors to a certain extent. Therefore, the dynamic evaluation of NAR during the ICU stay can make a difference. Furthermore, merely measuring NAR does not adequately reflect genuine levels of inflammation. Therefore, simultaneous measurement of other inflammatory factors would make a better demonstration of our conclusions. Last but not the least, to set up NAR as a prognostic biomarker, its clinical significance must further be verified.

Conclusions
We found that NAR level was associated with survival of CS. Furthermore, NAR appeared to be an independent and readily available prognostic biomarker of outcomes in patients with CS. However, further prospective studies with larger sample size are needed to confirm our findings.

Ethics approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Competing interests
The authors have no competing interests to declare.

Funding
No funding.

Acknowledgements
We acknowledge the support from the Second Affiliated Hospital of Wenzhou Medical University.

Availability of data and materials
All data in our study were extracted from a freely accessible database, the Medical    .34) NAR: neutrophil-albumin ratio; LOS_ICU: length of stay in intensive care unit; HR: heart rate; SBP: systolic blood pressure; DB respiratory rate; SPO2: percutaneous oxygen saturation; BUN: blood urea nitrogen; SCr: Serum creatinine; WBC: white blood INR: international normalized ratio; CAD: coronary heart disease; CHF: congestive heart failure; AF: atrial fibrillation; COPD: c distress syndrome; RRT: renal replacement therapy; SOFA: Sequential Organ Failure Assessment; SAPSII: Simplified Acute Ph Pvalue: a P < 0.05, b P < 0.01, c P < 0.001